Disorders of sex development: timing of diagnosis and management in a single large tertiary center.

BACKGROUND: We describe the phenotypic spectrum and timing of diagnosis and management in a large series of patients with disorders of sexual development (DSD) treated in a single pediatric tertiary center. METHODS: DSD patients who had visited our tertiary center during the survey period (between 2004 and 2014) were identified based on an ICD-10 inquiry, and their phenotypic and molecular genetic findings were recorded from patient charts. RESULTS: Among the 550 DSD patients, 53.3% had 46,XY DSD; 37.1% had sex chromosome DSD and 9.6% had 46,XX DSD. The most common diagnoses were Turner syndrome (19.8%, diagnosed at the mean age of 4.7 ± 5.5 years), Klinefelter syndrome (14.5%, 6.8 ± 6.2 years) and bilateral cryptorchidism (23.1%). Very few patients with 46,XY DSD (7%) or 46,XX DSD (21%) had molecular genetic diagnosis. The yearly rate of DSD diagnoses remained stable over the survey period. After the release of the Nordic consensus on the management of undescended testes, the age at surgery for bilateral cryptorchidism declined significantly (P < 0.001). CONCLUSIONS: Our results show that (i) Turner syndrome and Klinefelter syndrome, the most frequent single DSD diagnoses, are still diagnosed relatively late; (ii) a temporal shift was observed in the management of bilateral cryptorchidism, which may favorably influence patients' adulthood semen quality and (iii) next-generation sequencing methods are not fully employed in the diagnostics of DSD patients.

Anti-tumor necrosis factor treatment in cherubism--clinical, radiological and histological findings in two children.

Cherubism is a rare and disfiguring genetic disorder with excessive bone resorption and multilocular lesions in the mandible and/or maxilla. The disease-causing gain-of-function mutations in the SH3-binding protein 2 (SH3BP2) gene result in increased myeloid cell responses to macrophage colony stimulating factor and RANK ligand, formation of hyperactive osteoclasts (giant cells), and hyper-reactive macrophages that produce excessive amounts of the inflammatory cytokine tumor necrosis factor α (TNF-α). Recent findings in the cherubism mouse model suggest that TNF-α plays a major role in disease pathogenesis and that removal of TNF-α prevents development of the bone phenotype. We treated two children with cherubism with the TNF-α antagonist adalimumab for approximately 2.5 years and collected extensive clinical, radiological and histological follow-up data during the treatment. Histologically the treatment resulted in a significant reduction in the number of multinucleated giant cells and TNF-α staining positivity in both patients. As evaluated by computed tomography and magnetic resonance imaging, the lesions in Patient 1 showed either moderate enlargement (mandibular symphysis) or remained stable (mandibular rami and body, the maxilla). In Patient 2, the lesions in mandibular symphysis showed enlargement during the first 8 months of treatment, and thereafter the lesions remained unchanged. Bone formation and resorption markers remained unaffected. The treatment was well tolerated. Based on our findings, TNF-α antagonist may decrease the formation of pathogenic giant cells, but does not result in lesion regression or prevent lesion expansion in active cherubism. TNF-α modulator treatment thus does not appear to provide sufficient amelioration for patients suffering from cherubism.

Bone mineral density, body composition and bone turnover in patients with congenital hypogonadotropic hypogonadism.

Patients with congenital hypogonadotropic hypogonadism (HH) may have reduced peak bone mass in early adulthood, and increased risk for osteoporosis despite long-term hormonal replacement therapy (HRT). To investigate the relationship between HRT history and measures of bone health in patients with HH, we recruited 33 subjects (24 men, nine women; mean age 39.8 years, range: 24.0-69.1) with congenital HH (Kallmann syndrome or normosmic HH). They underwent clinical examination, were interviewed and medical charts were reviewed. Twenty-six subjects underwent dual-energy X-ray absorptiometry for evaluation of BMD of lumbar spine, hip, femoral neck and whole body; body composition and vertebral morphology were evaluated in 22 and 23 subjects, respectively. Circulating PINP, ICTP and sex hormone levels were measured. HRT history clearly associated to bone health: BMDs of lumbar spine, femoral neck, hip and whole body were lower in subjects (n = 9) who had had long (≥5 years) treatment pauses or low dose testosterone (T) treatment as compared to subjects without such history (n = 17; all p-values < 0.05). In addition, fat mass and body mass index (BMI) were significantly higher in men with deficient treatment history (median fat mass: 37.5 vs. 23.1%, p = 0.005; BMI: 32.6 vs. 25.2 kg/m(2), p < 0.05). Serum PINP correlated with ICTP (r(s) = 0.61; p < 0.005) in men, but these markers correlated neither with circulating T, nor with serum estradiol levels in women. In conclusion, patients with congenital HH require life-long follow-up to avoid inadequate HRT, long treatment pauses and further morbidity.

The striatocapsular infarction and its aftermaths.

Ischaemic stroke syndromes in the vascular territory of middle cerebral artery may have atypical presentation and radiographic findings because of the variable anatomy of that artery. Therefore, misdiagnosis of these syndromes as neoplastic or infectious processes is not uncommon. This case describes a 69-year-old comatose woman who was referred to us as having 'a brain tumour with massive surrounding oedema.' Further work-up revealed that she had a large left-sided lenticular nuclear infarction with some extension into the surrounding areas-the striatocapsular infarction.

Anatomical success rate of macular hole surgery with autologous platelet without internal-limiting membrane peeling.

AIM: To describe our experience and success rate of macular hole surgery with pars plana vitrectomy with autologous platelet and without internal limiting membrane peel. METHODS: Retrospective review of 56 consecutive patients who underwent macular hole surgery. RESULTS: Anatomical success was achieved in 55 out of 56 patients (98.2%). Functional success was achieved in 37 out of 56 patients (66.1%). A total of 21 patients (37.5%) achieved postoperative visual acuity of 6/12 or better. No intraoperative complications were encountered. Postoperative complications included cataract progression in eight eyes and raised intraocular pressure in 20 eyes. CONCLUSIONS: Our success rate was comparable to that reported in macular hole surgery incorporating internal limiting membrane (ILM) peel or with autologous platelet without ILM peel.

Intraindividual variability of infant whole-body plethysmographic measurements: effects of age and disease.

The intraindividual variability of whole-body plethysmographic measurements was studied in a large series of consecutive infants (N = 144), divided into two groups: a group of infants born very prematurely (PM, N = 63), with (N = 28) or without (N = 35) a history of bronchopulmonary dysplasia (BPD), and a group of infants with persistent respiratory symptoms (PRS, N = 81), i.e., wheezing (N = 53) or cough (N = 28). The intraindividual variability was determined within each test and between tests, separated by a 10-min interval. In both study groups, the between-test variability was significantly larger than that within tests. Expressed as the median coefficient of variation (CV), the between-test repeatabilities in the PRS group were 8.0% for thoracic gas volume (TGV), 17.5% for airway resistance (Raw), and 18.4% for specific airway conductance (sGaw), and in the PM group, 8.9% for TGV, 20.4% for Raw, and 20.7% for sGaw. However, the individual range of CVs was large, ranging from 3 to 19% for TGV and from 5 to 55% for sGaw. With respect to TGV, the difference between the groups was statistically significant (P = 0.03). In infants with a history of BPD, there was also a significant negative age dependency in CVs of sGaw (r = -0.50, P = 0. 009), showing larger variation among younger individuals. The presenting symptom (wheezing or cough) in the PRS group did not influence the measurement variability significantly, and neither did the degree of bronchial obstruction. We conclude that on a group basis, the repeatability of infant body plethysmographic measurements may be satisfactory for scientific studies demonstrating pharmacodynamic effects; however, the intraindividual measurement variability should be reported for each test conditions and for infant groups in each study. Due to the large range in individual variation and the influence of age and disease processes on the variation, for an individual child there is only questionable benefit from a given measurement, unless the intrasubject, between-test variability is assessed individually before interventions, such as a bronchodilation test.

Intrauterine creation and repair of pulmonary artery stenosis in the fetal lamb. Weight and ultrastructural changes of the ventricles.

Fetal lamb experimental models were employed for intrauterine creation and repair of pulmonary artery stenosis. The study group was composed of 51 fetal lambs including 29 models of pulmonary artery stenosis and 22 control lambs. Gestational age was 89 days at creation of pulmonary artery stenosis. Fourteen fetal lambs (Group A) were studied after creation of the stenosis at 131 days of gestation and compared to normal age-matched control lambs. The systolic right ventricular pressure was significantly higher after creation of pulmonary artery stenosis (76.6 +/- 17.8 versus 50.3 +/- 23.5 mm Hg), but the systolic pulmonary artery pressure was unchanged. The mean right ventricular weight and the mean right ventricular/left ventricular weight ratio were significantly greater after pulmonary artery stenosis than in normal control animals. The transverse myocyte diameter was not modified by pulmonary artery stenosis, but on electron microscopic study the myocytes appeared mature. Ten lambs (Group B) underwent intrauterine repair of pulmonary artery stenosis at 131 days of gestation without cardiopulmonary bypass. The pulmonary artery was clamped and patched. Immediately after repair the right ventricular pressure fell significantly from 85.8 +/- 18.9 to 62.2 +/- 14.6 mm Hg. At birth, 7 +/- 6 days after repair, Group B was compared to Group C (unrepaired pulmonary artery stenosis, five fetuses) and to normal control lambs. The mean right ventricular weight and the mean right ventricular/left ventricular weight ratio were not statistically different in Group B and in the control group. There were no ultrastructural changes after intrauterine repair. We conclude that intrauterine creation of pulmonary artery stenosis causes right ventricular hypertrophy with more mature myocytes. Intrauterine repair of pulmonary artery stenosis is feasible without cardiopulmonary bypass and rapidly abolishes the preponderance of right ventricular weight over left ventricular weight.

Experimental cardioplasty using the latissimus dorsi muscle flap.

This study was undertaken to examine the possibility of using the latissimus dorsi muscular flap, divided in two parts thus covering the surfaces of the heart, and inserting it into the thoracic cavity by means of a segmental resection of the second rib. After cadaver case studies, 15 operations were performed on 5 Beagle dogs. The first group of 5 operations consisted of a latissimus dorsi flap graft over the heart. The second group and third group of operations (3 and 6 months later) consisted of reoperating for muscular and cardiac biopsies and electrical stimulation tests on the heart-muscle complex. The latissimus dorsi flap provided a sizable mass of contractile tissue. The haemodynamic studies showed no compressive or constrictive phenomenon of the muscle on the heart and revealed the preservation of an appropriate cardiac output for short intervals of time (2 hours), through phasic electrostimulation of the flap. The histopathological studies showed conserved muscular structure. The technical feasibility, histological adaptability and electrophysiological properties of this muscular flap makes it appropriate to develop a functional stimulation programme and perhaps adequate for the treatment of dysplasic, ischemic, tumoral and other acquired or congenital myocardial diseases.